Download LoopDiuretics_Final v8_0 _SB comments_

Drug Shortage Alert
11/15/2012
Recommendations and information provided in Drug Shortage Alerts are compiled by
experts in the field. Practitioners always are advised to consult with staff to ensure
response to any drug shortage is in line with internal policies and procedures.
Drug Shortages Alert
Loop Diuretics (furosemide, bumetanide, torsemide)
Introduction
The Society of Critical Care Medicine’s Drug Shortages Task Force has identified a
shortage leading to variable availability of intravenous loop diuretics, including
bumetanide, furosemide, and torsemide.
§ Furosemide Injection
o The primary factors contributing to the shortage of this agent include
manufacturing delays and an inability to meet market demand. Furthermore, one
manufacturer has discontinued production.
§ Torsemide Injection
o Two manufacturers have approval for production of torsemide injection, but
manufacturing delays have resulted in limited availability. An additional
manufacturer has discontinued the product.
§ Bumetanide Injection
o Reliable availability of this agent is limited by suspension of production
and/or distribution among only four manufacturers.
§ No superiority in dose response exists among the intravenous loop diuretics when
used at equipotent doses. However, safety must be considered when switching
between drugs with different potencies. In addition, issues with practitioner
familiarity need to be considered.
§ This alert provides information on conversion/equivalency between loop diuretics,
alternative dosing strategies, and a step-wise approach to diuretic therapy.
§ Additional information and shortage updates can be accessed at
http://www.ashp.org/menu/PracticePolicy/ResourceCenters/DrugShortages.aspx.
Management Strategies
§ Step-wise approach to diuretic therapy:
1. Attempt oral loop therapy if appropriate and augment dose/frequency as indicated
based on clinical response (refer to Table 1).
a. Intravenous (IV) diuretics should be given for acute pulmonary
congestion.
b. Torsemide or bumetanide have good bioavailability and may be preferred
as oral agents.
2. If the patient is not responding adequately to escalated oral therapy or if oral
therapy is inappropriate, switch to IV.
3. Escalate IV dose/frequency.
4. If inadequate response at escalated dose/frequency, consider one of the following:
a. Add a thiazide/thiazide-like diuretic to intermittent IV loop diuretic (refer
to Table 3).*
b. Change to continuous infusion loop diuretic based on availability (refer to
Table 2).*
*Choosing between these two approaches depends on the clinical
condition being treated and evidence of loop diuretic resistance (lack of
response to intravenous furosemide doses of ≥160 mg or equivalent).
5. If patient remains volume overloaded with inadequate response to escalated
therapy, initiate continuous infusion loop diuretic and consider addition of a
thiazide/thiazide-like diuretic (refer to Table 3).
Table 1. Loop Diuretic Comparison to Furosemide
Loop Diuretic
Bioavailability*
Equivalent
Dosing*
1 mg
1 mg
Not Available
20 mg
20 mg
40 mg
50 mg
Dosing
Frequency
Daily to Q12H
Daily to Q12H
Bumetanide (Bumex®) IV
100%
®
Bumetanide (Bumex ) Oral
80%-90%
Torsemide (Demadex®) IV
Torsemide (Demadex®) Oral
80%-100%
Daily to Q12H
Furosemide (Lasix®) IV
100%
Daily to Q8H
®
Furosemide (Lasix ) Oral
~50% (varies)
Daily to Q8H
Ethacrynic Acid (Edecrin®) IV
100%
Daily to Q8H
®
Ethacrynate Sodium (Edecrin )
100%
50 mg
Daily to Q8H
Oral
*Bioavailability and dose response depends on disease state and prior exposure to
diuretics.
Table 2. Equipotent Dosing of Continuous Loop Diuretic Infusions
Furosemide (Lasix®)
Bumetanide (Bumex®)
2.5 mg/hr
0.125 mg/hr
5 mg/hr
0.25 mg/hr
7.5 mg/hr
0.375 mg /hr
10 mg/hr
0.5 mg /hr
20 mg/hr
1 mg/hr
40 mg/hr
2 mg /hr
Table 3. Thiazide and Thiazide-like Diuretics
Thiazide-like Diuretic
Bioavailability*
Equivalent
Dosing*
250 mg
25 mg
Recommended
Dosing Intervals
Daily to Q12H
Daily to Q12H
Chlorothiazide (Diuril®) IV
100%
Hydrochlorothiazide Oral
65%-75%
Metolazone (Zaroxolyn®)
40%-65%
2.5 mg
Daily
Oral**
* Bioavailability and dose response depends on disease state and prior exposure to
diuretics
** Long half-life and greater risk of electrolyte abnormalities
Pharmacotherapeutic Considerations
§ All drugs within the loop diuretic class have a similar time to onset, peak effect and
duration of action. However, differences exist in metabolism, bioavailability, halflife, and effect of food on absorption (refer to Table 4).
§ Bumetanide, ethacrynic acid, and torsemide have more predictable bioavailability
compared to furosemide.
§ Route of Administration
o Oral administration is altered in the presence of gastrointestinal edema,
gastroparesis and delayed gastric emptying.
o Administration by the IV route may result in improved efficacy, except in
the case of ethacrynic acid. If continuous infusion is used, a loading dose
of a loop diuretic should be administered before initiating the continuous
infusion or when the rate is increased to decrease the time for the drug’s
onset of action.
o The loading dose and initial infusion rate are usually determined by the
patient’s renal function and previous dose response. In diuretic-naïve
patients, the recommended initial loading dose for IV furosemide is 40 mg
(maximum 200 mg) and bumetanide is 1 mg (maximum 5 mg).
§ Combination therapy with thiazide diuretic
o No thiazide diuretic has proven superiority for concomitant use with loop
diuretics.
o Thiazides have a longer half-life than loop diuretics, resulting in
prolonged diuresis.
Table 4. Pharmacokinetics of Loop Diuretics
Property
Bumetanide Ethacrynic acid
(Bumex®)
(Edecrin®)
Onset of action (min)
Oral
30-60
30-60
IV
2-3
5
Time to peak effect (min)
15-30
15-30
Half-life (hours)
Renal dysfunction
Hepatic dysfunction
Heart failure
Metabolism
Effect of food on
absorption
1
1.6
2.3
1.3
2
50% hepatic
hepatic
Decreased
None
Furosemide
(Lasix®)
Torsemide
(Demadex®)
30-60
5
30-60
Unavailable IV
30
1.5-2
2.8
2.5
2.7
50% renal
conjugation
60
3.4
4-5
8
6
Decreased
80% hepatic
None
Safety Implications
§ Pertinent adverse effects include hypovolemia, hypotension, decreased serum
electrolytes (i.e., sodium, potassium, magnesium, chloride, and calcium), and
metabolic alkalosis. Individualized dosing and close monitoring is therefore
recommended.
§ Loop diuretics can cause ototoxicity as a result of high peak concentrations. To
minimize this adverse effect:
o Consider administration via continuous infusion as opposed to high bolus
doses.
o Avoid ethacrynic acid, which has the greatest risk of ototoxicity.
§ A sulfonamide allergy without a previous diuretic reaction should not prohibit
administration of a loop diuretic containing a sulfa moiety (furosemide, bumetanide,
torsemide). In rare instances of a reaction, ethacrynic acid could be used as an
alternative.
Impact on ICU Care
§ Intravenous furosemide is commonly used in the ICU. However, there is not enough
evidence to support the use of one loop diuretic over another.
§ Healthcare providers (i.e., physicians, affiliate providers, pharmacists, and nurses)
should be familiar with differences in dosing between loop diuretics in order to
prevent potential dosing errors.
§ Most loop diuretics are available in a generic formulation, but there are differences in
cost (refer to Table 5).
Table 5. Acquisition Costs for Diuretics
Drug
Strength
®
Bumetanide (Bumex )
1 mg
Oral
1 mg/4 mL
IV
Furosemide (Lasix®)
40 mg
Oral
40 mg/4 mL
IV (10 mg/mL)
Torsemide (Demadex®)
Oral
10 mg
Ethacrynic Acid
25 mg
(Edecrin®)*
50 mg
Oral
IV
Chlorothiazide (Diuril®)
IV
500 mg
Hydrochlorothiazide
PO
25 mg
®
Metolazone (Zaroxolyn )
PO
5 mg
*No generic available
Average Wholesale Price ($)
0.41
1.01
0.21
1.01
0.70
4.71
912.21
372.13
0.15
1.69
References
1. Asare K. Management of loop diuretic resistance in the intensive care unit. Am J
Health-Syst Pharm. 2009;66(18):1635-1640.
2. Brater DC. Diuretic therapy. N Engl J Med. 1998;339(6):387-395.
3. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute
decompensated heart failure. N Engl J Med. 2011;364(9):797-805.
4. Wargo KA, Banta WM. A comprehensive review of the loop diuretics: should
furosemide be first line? Ann Pharmacother. 2009;43(11):1836-1847.
5. Feldman DS, Elton TS, Pickworth K. Chapter 23: Diuretics: utility and limitations.
In: Kirklin JK, Banner N, Jessup M, eds. ISHLT Monograph Series Volume 3:
Advanced Heart Failure, Part 1. New York, NY: Elsevier; 2009.
Contributed By
Erik E. Abel, PharmD, BCPS
Cardiology/Cardiothoracic Surgery Specialty Pharmacist
Clinical Assistant Professor
Department of Pharmacy
The Ohio State University Wexner Medical Center
Columbus, Ohio, USA
Stacey L. Folse, PharmD, MPH, BCPS
Clinical Pharmacy Specialist, Medical ICU
PGY 2 Residency Director, Critical Care
Emory University Hospital
Adjunct Clinical Assistant Professor
Mercer University School of Pharmacy and Health Sciences
Atlanta, Georgia, USA
Pamela K. Burcham, PharmD, BCPS
Cardiology/Cardiothoracic Surgery Specialty Pharmacist
Department of Pharmacy
The Ohio State University Wexner Medical Center
Columbus, Ohio, USA
Antoinette Spevetz, MD, FACP, FCCM
Associate Professor of Medicine
Designated Institution Official, Graduate Medical Education
Associate Director, MSICU for Operations
Director, Intermediate Care Unit
Associate Director, Internal Medicine Residency Program
Section of Critical Care Medicine
Cooper University Hospital
Camden, New Jersey, USA
Kerry Pickworth, PharmD
Cardiology Specialty Pharmacist
Associate Professor
Department of Pharmacy
The Ohio State University Wexner Medical Center
Columbus, Ohio, USA
Reviewers:
Scott Bolesta, PharmD, BCPS
Gail Gesin, PharmD
John Lewin, PharmD, MBA